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Role of Chemotherapy Dose Intensification in the Treatment of Advanced Ovarian Cancer

Role of Chemotherapy Dose Intensification in the Treatment of Advanced Ovarian Cancer

Cisplatin (Platinol) has been the most active agent against ovarian cancer. The question of a relationship between platinum dose and response remains unresolved. Eight prospective, randomized studies have examined the role of platinum dose intensity in the front-line management of newly diagnosed ovarian cancer. In none of these studies did the dose intensities achieved exceed twice that of a standard regimen. Additionally, none of these studies addressed the role of truly high-dose therapy requiring hematologic support. Recent evidence supports the idea that more substantial intensification of platinum drug delivery may be achieved by intraperitoneal administration. Similarly, very-high-dose platinum-based chemotherapy with autologous bone marrow transplantation has been shown to produce high levels of response in patients refractory to conventional-dose platinum. However, these high response rates have been achieved at the cost of considerable morbidity and generally have been of short duration. The use of peripheral blood progenitor cells may now allow us to evaluate further the role of platinum dose intensification and is currently under investigation.

Introduction

Despite the advances made in the treatment of advanced ovarian cancer, the prognosis for patients with advanced disease remains disappointing, with reported 5-year survival rates of 21% [1]. Patients with ovarian cancer demonstrate high response rates and occasional cures but frequent relapses. One method of improving the curative potential of primary therapy may involve the intensification of drug dosage.

Retrospective Analyses

In their original retrospective analysis, Levin and Hryniuk explored the role of dose intensity in the treatment of advanced ovarian cancer [2]. They were able to demonstrate a statistically significant correlation between increasing the dose intensity (defined as the amount of drug delivered per unit of time [mg/m²/week]) of cisplatin and both the response rate and overall survival [2]. Analysis of the dose intensity of other drugs, such as cyclophosphamide (Cytoxan, Neosar) and doxorubicin failed to reveal a significant correlation between increasing the dose intensity and overall response.

This retrospective analysis was based primarily on published trials involving mainly patients with suboptimally debulked stage III and IV disease, with nearly 90% of patients having residual disease of more than 2 cm. In this meta-analysis, the "standard" regimen employed a cisplatin dose equivalent to 15 mg/m²/week. Thus, the demonstrated dose-response relationship holds true over a range of 6 to 12 mg/m²/week. This is equivalent to a total dose of approximately 36 mg/m² over 3 weeks and thus is lower than the commonly employed "low-dose" cisplatin regimen of 50 mg/m² every 3 weeks. This analysis appears to provide support for optimal versus suboptimal dosing as opposed to high versus standard dosing of cisplatin.

A recent updated analysis of their findings has been published [3]. They analyzed data from a total of 18 platinum-containing regimens used in 9 randomized trials in addition to data from the 60 groups of patients analyzed in the previous study. This analysis confirmed that the association between outcome and dose intensity was statistically significant for both cisplatin alone and cisplatin in combination-therapy regimens. The association for cyclophosphamide as a single agent was of borderline significance (P = 0.06). For doxorubicin, when used in combination therapy regimens, the association was again of borderline significance; however, there were insufficient data to assess doxorubicin's effect as a single agent. Additionally, it was recognized that in all of the combination regimens evaluated, doxorubicin was used at a relative dose intensity of 10 to 15 mg/m²/week, which is lower than the 25 mg/m²/week recommended for its use as a single agent.

Randomized Trials

The debate as to the true value of dose-intensive therapy continues to be hotly contested. We now have data from a number of randomized trials addressing the issue of dose intensity (

Table 1) [4-11]. However, they have served to cloud the issue further.

In a study by Kaye et al [4], at 18 months, a significant survival advantage of 73% vs 48% was noted in favor of the high-dose arm. This resulted in early discontinuance of the study. Patients on the high-dose arm of this study received 1.3 times the dose intensity of the low-dose arm. Additionally, the high-dose arm delivered a 66% greater total dose of cisplatin than the low-dose arm (600 mg/m² vs 300 mg/m²) [3]. Analysis of this study is complicated further by the fact that 30% of the patients treated had early-stage ovarian cancer and were treated in an adjuvant setting. However, analysis of the patients treated with advanced disease still showed a difference in favor of the high-dose arm.

The Gynecologic Oncology Group has performed a similar study. In this study of 460 patients with suboptimally debulked disease, no significant differences in progression-free or overall survival were seen [5]. A twofold increase in dose intensity of both cisplatin and cyclophosphamide (cisplatin/cyclophosphamide 50/500 mg/m² every 3 weeks x 8 cycles vs 100/1,000 every 3 weeks x 4 cycles) was achieved in the high-dose arm with identical total doses of drug being delivered.

Despite a number of other randomized trials now reported in the literature (

Table 1), an overview of these trials fails to determine the true value of dose intensity in the treatment of advanced ovarian cancer. From these studies, however, some important points can be made. Studies focusing on patients with suboptimally debulked (more than 1 cm residual) disease have consistently reported negative results in terms of statistically significant improvement in response rates and overall survival [5,11]. Furthermore, studies focusing on patients with optimally debulked disease have reported positive end points in terms of both response and overall survival. In three of the studies mentioned, the more dose-intensive treatment arm received fewer overall cycles of chemotherapy [5,9,10]. The studies that employed this design were reported to be negative, and none of the "positive" studies employed this treatment design. The studies resulting in positive outcomes focused on not only increased total dose but also increased dose intensity, indicating that both factors are of importance.

Dose-Intensive Platinum Therapy--In none of the randomized studies reported did patients receive true high-dose chemotherapy. An important feature of dose intensity is the degree of dose intensification required to obtain a clinical effect. In the analysis by Levin and colleagues, the dose intensity achieved ranged from 0.3 to 1.1 [3]. If it is true that the benefit of dose-intensive therapy lies in its ability to overcome relative drug resistance, the in vitro models available suggest that a more than fivefold increase in dose intensity would be required to overcome this resistance [12].

Based on the initial work of Levin and associates, the focus of strategies to improve dose intensity has been consistently on platinum delivery. It is accepted that by increasing the dose of platinum delivered, responses can be obtained in tumors previously refractory to platinum therapy (

Table 2) [13-17]. With the advent of carboplatin (Paraplatin), a platinum analog with a more benign toxicity profile, investigators' attention turned to attempts to increase the dose intensity of platinum using carboplatin.

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